US11174230B2 - (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates as potential anticancer agents - Google Patents

(E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates as potential anticancer agents Download PDF

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US11174230B2
US11174230B2 US16/071,105 US201716071105A US11174230B2 US 11174230 B2 US11174230 B2 US 11174230B2 US 201716071105 A US201716071105 A US 201716071105A US 11174230 B2 US11174230 B2 US 11174230B2
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acrylamido
phenoxy
methylpicolinamide
methyl
picolinamide
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Ahmed Kamal
Velma Ganga REDDY
Riyaz Syed
Suresh Babu Korrapati
Poornachandra Yedla
Ganesh Kumar Chityal
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula A.
  • R is selected from
  • R 1 to R 5 is independently selected from the group consisting of H, Cl, F, Br, CH 3 , C 2 H 5 , CH(CH 3 ) 2 , OCH 3 , CF 3 , OCF 3 , OH, NO 2 or CN;
  • X is selected from O, N or S.
  • present invention relates to the synthesis and biological evaluation of (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula A as potential anticancer agents.
  • Protein tyrosine kinases are presently familiar as significant molecular targets for drug development in the treatment of several disorders, predominantly in the treatment of proliferative disorders. Dysregulation of tyrosine kinase activity has emerged as a major mechanism by which cancer cells avoid normal physiological constraints on growth, proliferation and survival.
  • Raf proteins are subject to complex regulation, which is reflected by the presence of numerous phosphorylation sites that are distributed throughout the proteins. Some of the sites are conserved in all three isoforms, which indicates common mechanisms of regulation, but others are not conserved, which shows that these proteins can be independently regulated. There are three Raf isoforms in mammals, A-Raf, B-Raf and C-Raf, all of which can act as downstream effectors of RAS. Although they show considerable sequence similarities, they also exhibit distinct roles in development, in addition to significant biochemical and functional differences. Raf proteins are subject to complex regulation, which is reflected by the presence of numerous phosphorylation sites that are distributed throughout the proteins.
  • B-Raf is part of a conserved signal transduction pathway that regulates cellular responses to extra cellular signals (Wellbrock et al, Mol. Cell. Boil., 2004, 5, 875-885).
  • B-Raf is mutated in around 7% of human cancers, extensively such as melanoma, ovarian and thyroid cancers (Davies et al, Cancer Cell., 2003, 2, 95-98), in this the most common mutation is a glutamic acid for valine substitution at position 600 (V600E) (Niculescu-Duvas er cr/., J. Med. Chem., 2006, 49, 407-416).
  • Sorafenib is a small-molecule multi-kinase inhibitor that inhibits kinases such as Raf kinase, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR)- ⁇ tyrosine kinases (Wilhelm et al, Cancer Res., 2004, 64(19):7099-109).
  • This kinase inhibitor having flat, aromatic molecules which mimic the adenine group of ATP which binds to a highly conserved ATP-binding pocket to inhibit kinase function. It is a bi-aryl urea which inhibits cell surface tyrosine kinase receptors (e.g.
  • vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta and downstream intracellular serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in inhibition of tumor-cell proliferation, angiogenesis and increases the rate of apoptosis in a wide range of tumor models (Chang and coworkers, Cancer Chemother Pharmacol., 2007; 59(5): 561-74).
  • sorafenib demonstrated multi-kinase inhibitory activities with potent anti-antigenic properties via the inhibition of pro-angiogenic receptor tyrosine kinases (RTKs), such as the VEGFR.
  • RTKs pro-angiogenic receptor tyrosine kinases
  • sorafenib displays multi-inhibitory action in the RAF/MEK/ERK pathway and RTKs to combat tumour angiogenesis.
  • This drug has shown marked clinical efficiency and safety in advanced renal cell and hepatocellular carcinoma, it has been approved for the treatment of these cancers in patients (Asakawa and coworkers, Bioorg. Med. Chem. Lett., 2011, 21, 2220-2223).
  • the present work involves the synthesis of new molecules based on sorafenib ring system.
  • One of the major issues of selectivity in the development of anticancer agents has been addressed by these molecules as they are highly selective towards some specific cancer cell lines.
  • the main objective of the present invention is to provide (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula A as potential antitumor agents.
  • Another object of the present invention is to provide a process for the preparation of (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula A.
  • the FIGURE represents process steps for the preparation of compound of formula A wherein reagents and conditions are as follows: (i) KOt-Bu, K 2 CO 3 , DMF, 80° C., 4 h; (ii) EDCI, HOBT, DMF, 0° C.-room temperature (20 to 30° C.), 12 h.
  • R is selected from
  • R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of H, Cl, F, Br, CH 3 , C 2 H 5 , CH(CH 3 ) 2 , OCH 3 , CF 3 , OCF 3 , OH, NO 2 or CN;
  • X is selected from O, N or S.
  • structural formulae of the representative compounds of formula A are:
  • said compound exhibit significant anticancer activity as antitumour antibiotics against cancer cell lines selected from the group consisting of non-small cell lung cancer, colon cancer, prostate cancer, ovarian cancer and liver cancer.
  • IC 50 value of in vitro anti-cancer activity of formula A is in the range of 8 to 13 ⁇ M.
  • present invention provides a process for the preparation of compounds of formula A comprising the steps of:
  • R is selected from
  • R 1 to R 5 is selected from the group consisting of H, Cl, F, Br, CH 3 , C 2 H 5 , CH(CH 3 ) 2 , OCH 3 , CF 3 , OCF 3 , OH, NO 2 or CN;
  • X is selected from O, N or S.
  • Aromatic and hetero cyclic substituted acrylic acids compound of formula 4a-z and 5a-aj are as follow:
  • the (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of general formulae 6a-6z and 7a-7aj have been evaluated for their cytotoxicity in selected human cancer cell lines i.e., lung (A549), prostate (DU-145), ovarian (SKOV3) and liver (HepG2) using MTT assay and the values obtained were compared to a standard drug sorafenib, with the concentration (treatment done at ranging from 10 ⁇ 4 to 10 ⁇ 8 M) of the compound produces to 50% inhibition of cell growth (IC 50 ) as shown in Table 1.
  • the screening results suggested that the selected compounds 6b, 6c, 6d, 6e, 6g, 6l, 6m, 6o, 6p, 6q, 6t, 6z, 7b and 7g exhibit significant cytotoxicity against a different set of human cancer cell lines.
  • the IC 50 values (in ⁇ M) for compounds 6b, 6c, 6d, 6e, 6g, 6l, 6m, 6o, 6p, 6q, 6t, 6z, 7b and 7g have been illustrated in Table 1.
  • the compounds 6b, 6l, 6d, 6e and 7b were more potent than the other compounds like 6c, 6g, 6m, 6o, 6p, 6q, 6z and 7g.
  • the IC 50 values (in ⁇ M) for the compounds 6b, 6d, 6e, 6l and 7b against HepG2 (liver cancer) cell line were 9.5, 10.2, 10.1, 9.6 and 10.2 ⁇ M respectively.
  • the present invention provides some new (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates useful as antitumor agents.
  • the synthesized compounds have shown significant anticancer activity.

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Abstract

The present invention relates to a compound of formula A useful as potential anticancer agents against human cancer cell lines and process for the preparation thereof.
Figure US11174230-20211116-C00001

Description

FIELD OF THE INVENTION
The present invention relates to (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula A.
Figure US11174230-20211116-C00002
wherein R is selected from
Figure US11174230-20211116-C00003
R1 to R5 is independently selected from the group consisting of H, Cl, F, Br, CH3, C2H5, CH(CH3)2, OCH3, CF3, OCF3, OH, NO2 or CN;
X is selected from O, N or S.
Particularly, present invention relates to the synthesis and biological evaluation of (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula A as potential anticancer agents.
BACKGROUND OF THE INVENTION
Protein tyrosine kinases are presently familiar as significant molecular targets for drug development in the treatment of several disorders, predominantly in the treatment of proliferative disorders. Dysregulation of tyrosine kinase activity has emerged as a major mechanism by which cancer cells avoid normal physiological constraints on growth, proliferation and survival.
Raf proteins are subject to complex regulation, which is reflected by the presence of numerous phosphorylation sites that are distributed throughout the proteins. Some of the sites are conserved in all three isoforms, which indicates common mechanisms of regulation, but others are not conserved, which shows that these proteins can be independently regulated. There are three Raf isoforms in mammals, A-Raf, B-Raf and C-Raf, all of which can act as downstream effectors of RAS. Although they show considerable sequence similarities, they also exhibit distinct roles in development, in addition to significant biochemical and functional differences. Raf proteins are subject to complex regulation, which is reflected by the presence of numerous phosphorylation sites that are distributed throughout the proteins. In particular, the high basal kinase activity of B-Raf may explain why mutated forms of only this isoform have been found in human cancers. B-Raf is part of a conserved signal transduction pathway that regulates cellular responses to extra cellular signals (Wellbrock et al, Mol. Cell. Boil., 2004, 5, 875-885). B-Raf is mutated in around 7% of human cancers, extensively such as melanoma, ovarian and thyroid cancers (Davies et al, Cancer Cell., 2003, 2, 95-98), in this the most common mutation is a glutamic acid for valine substitution at position 600 (V600E) (Niculescu-Duvas er cr/., J. Med. Chem., 2006, 49, 407-416).
Sorafenib is a small-molecule multi-kinase inhibitor that inhibits kinases such as Raf kinase, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR)-β tyrosine kinases (Wilhelm et al, Cancer Res., 2004, 64(19):7099-109). This kinase inhibitor having flat, aromatic molecules which mimic the adenine group of ATP which binds to a highly conserved ATP-binding pocket to inhibit kinase function. It is a bi-aryl urea which inhibits cell surface tyrosine kinase receptors (e.g. vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta) and downstream intracellular serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in inhibition of tumor-cell proliferation, angiogenesis and increases the rate of apoptosis in a wide range of tumor models (Chang and coworkers, Cancer Chemother Pharmacol., 2007; 59(5): 561-74). However, the structural features of sorafenib demonstrated multi-kinase inhibitory activities with potent anti-antigenic properties via the inhibition of pro-angiogenic receptor tyrosine kinases (RTKs), such as the VEGFR. As a result, sorafenib displays multi-inhibitory action in the RAF/MEK/ERK pathway and RTKs to combat tumour angiogenesis. This drug has shown marked clinical efficiency and safety in advanced renal cell and hepatocellular carcinoma, it has been approved for the treatment of these cancers in patients (Asakawa and coworkers, Bioorg. Med. Chem. Lett., 2011, 21, 2220-2223). The present work involves the synthesis of new molecules based on sorafenib ring system. One of the major issues of selectivity in the development of anticancer agents has been addressed by these molecules as they are highly selective towards some specific cancer cell lines. In continuation of these efforts and the interest in this laboratory structural modifications of the sorafenib, an efficient access to the construction of some new (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates (6a-z to 7a-aj) with improved cytotoxic activity in certain cell lines is described.
Figure US11174230-20211116-C00004
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula A as potential antitumor agents.
Another object of the present invention is to provide a process for the preparation of (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula A.
BRIEF DESCRIPTION OF THE DRAWING
The FIGURE represents process steps for the preparation of compound of formula A wherein reagents and conditions are as follows: (i) KOt-Bu, K2CO3, DMF, 80° C., 4 h; (ii) EDCI, HOBT, DMF, 0° C.-room temperature (20 to 30° C.), 12 h.
SUMMARY OF THE INVENTION
Accordingly, present invention provides compound of formula A
Figure US11174230-20211116-C00005
wherein R is selected from
Figure US11174230-20211116-C00006
R1, R2, R3, R4 and R5 is independently selected from the group consisting of H, Cl, F, Br, CH3, C2H5, CH(CH3)2, OCH3, CF3, OCF3, OH, NO2 or CN;
X is selected from O, N or S.
In an embodiment of the present invention, (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula A represented by the compounds of general formulae 6a-z to 7a-aj which are as follow:
  • (E)-4-(4-(3-(2-methoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6a);
  • (E)-4-(4-(3-(4-methoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6b);
  • (E)-4-(4-(3-(2,3-dimethoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6c);
  • (E)-N-methyl-4-(4-(3-(3,4,5-trimethoxyphenyl)acrylamido)phenoxy)picolinamide (6d);
  • (E)-4-(4-(3-(2,5-dimethoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6e);
  • (E)-4-(4-(3-(3,4-dimethoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6f);
  • (E)-4-(4-(3-(3-hydroxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6g);
  • (E)-4-(4-(3-(4-hydroxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6h);
  • (E)-4-(4-(3-(3-hydroxy-4-methoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6i);
  • (E)-4-(4-(3-(2-chlorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6j);
  • (E)-4-(4-(3-(3-chlorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6k);
  • (E)-4-(4-(3-(4-chlorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6l);
  • (E)-4-(4-(3-(3,4-dichlorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6m);
  • (E)-4-(4-(3-(3-fluorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6n);
  • (E)-4-(4-(3-(4-fluorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6o);
  • (E)-4-(4-(3-(2,4-difluorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6p);
  • (E)-4-(4-(3-(3,4-difluorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6q);
  • (E)-N-methyl-4-(4-(3-(2-(trifluoromethyl)phenyl)acrylamido)phenoxy)picolinamide (6r);
  • (E)-N-methyl-4-(4-(3-(3-(trifluoromethyl)phenyl)acrylamido)phenoxy)picolinamide (6s);
  • (E)-N-methyl-4-(4-(3-(4-(trifluoromethyl)phenyl)acrylamido)phenoxy)picolinamide (6t);
  • (E)-N-methyl-4-(4-(3-(2-(trifluoromethoxy)phenyl)acrylamido)phenoxy)picolinamide (6u);
  • (E)-N-methyl-4-(4-(3-(3-(trifluoromethoxy)phenyl)acrylamido)phenoxy)picolinamide (6v);
  • (E)-N-methyl-4-(4-(3-(4-(trifluoromethoxy)phenyl)acrylamido)phenoxy)picolinamide (6w);
  • (E)-4-(4-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)acrylamido)phenoxy)-N-methylpicolinamide (6x);
  • (E)-4-(4-(3-(4-chloro-3-(trifluoromethoxy)phenyl)acrylamido)phenoxy)-N-methylpicolinamide (6y);
  • (E)-N-methyl-4-(4-(3-(4-nitrophenyl)acrylamido)phenoxy)picolinamide (6z);
  • (E)-4-(4-(3-(1H-pyrrol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7a);
  • (E)-4-(4-(3-(furan-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7b);
  • (E)-N-methyl-4-(4-(3-(5-methylfuran-2-yl)acrylamido)phenoxy)picolinamide (7c);
  • (E)-4-(4-(3-(5-ethylfuran-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7d);
  • (E)-4-(4-(3-(3-bromofuran-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7e);
  • (E)-N-methyl-4-(4-(3-(5-nitrofuran-2-yl)acrylamido)phenoxy)picolinamide (7f);
  • (E)-N-methyl-4-(4-(3-(thiophen-2-yl)acrylamido)phenoxy)picolinamide (7g);
  • (E)-4-(4-(3-(4-bromothiophen-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7h);
  • (E)-N-methyl-4-(4-(3-(3-methylthiophen-2-yl)acrylamido)phenoxy)picolinamide (7i);
  • (E)-4-(4-(3-(5-cyanothiophen-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7j);
  • (E)-N-methyl-4-(4-(3-(4-methylthiophen-2-yl)acrylamido)phenoxy)picolinamide (7k);
  • (E)-N-methyl-4-(4-(3-(5-methylthiophen-2-yl)acrylamido)phenoxy)picolinamide (7l);
  • (E)-4-(4-(3-(benzofuran-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7m);
  • (E)-4-(4-(3-(7-methoxybenzofuran-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7n);
  • (E)-4-(4-(3-(benzo[b]thiophen-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7o);
  • (E)-4-(4-(3-(3-bromobenzo[b]thiophen-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7p);
  • (E)-N-methyl-4-(4-(3-(3-methylbenzo[b]thiophen-2-yl)acrylamido)phenoxy)picolinamide (7q);
  • (E)-4-(4-(3-(3-chlorobenzo[b]thiophen-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7r);
  • (E)-N-methyl-4-(4-(3-(5-methylbenzo[b]thiophen-2-yl)acrylamido)phenoxy)picolinamide (7s);
  • (E)-N-methyl-4-(4-(3-(4-methylbenzo[b]thiophen-2-yl)acrylamido)phenoxy)picolinamide (7t);
  • (E)-4-(4-(3-(1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7u);
  • (E)-N-methyl-4-(4-(3-(7-methyl-1H-indol-3-yl)acrylamido)phenoxy)picolinamide (7v);
  • (E)-4-(4-(3-(7-ethyl-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7w);
  • (E)-4-(4-(3-(6-isopropyl-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7x);
  • (E)-4-(4-(3-(5-chloro-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7y);
  • (E)-4-(4-(3-(6-chloro-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7z);
  • (E)-4-(4-(3-(5-fluoro-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7aa);
  • (E)-4-(4-(3-(6-fluoro-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7ab);
  • (E)-4-(4-(3-(5-bromo-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7ac);
  • (E)-4-(4-(3-(6-bromo-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7ad);
  • (E)-4-(4-(3-(5-cyano-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7ae);
  • (E)-4-(4-(3-(6-cyano-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7af);
  • (E)-N-methyl-4-(4-(3-(5-methyl-1H-indol-3-yl)acrylamido)phenoxy)picolinamide (7ag);
  • (E)-N-methyl-4-(4-(3-(6-methyl-1H-indol-3-yl)acrylamido)phenoxy)picolinamide (7ah);
  • (E)-N-methyl-4-(4-(3-(5-nitro-1H-indol-3-yl)acrylamido)phenoxy)picolinamide (7ai);
  • (E)-N-methyl-4-(4-(3-(6-nitro-1H-indol-3-yl)acrylamido)phenoxy)picolinamide (7aj).
In another embodiment of the present invention, structural formulae of the representative compounds of formula A are:
Figure US11174230-20211116-C00007
Figure US11174230-20211116-C00008
Figure US11174230-20211116-C00009
Figure US11174230-20211116-C00010
Figure US11174230-20211116-C00011
Figure US11174230-20211116-C00012
Figure US11174230-20211116-C00013
Figure US11174230-20211116-C00014
Figure US11174230-20211116-C00015
In yet another embodiment of the present invention, said compound exhibit significant anticancer activity as antitumour antibiotics against cancer cell lines selected from the group consisting of non-small cell lung cancer, colon cancer, prostate cancer, ovarian cancer and liver cancer.
In yet another embodiment of the present invention, IC50 value of in vitro anti-cancer activity of formula A is in the range of 8 to 13 μM.
In yet another embodiment, present invention provides a process for the preparation of compounds of formula A comprising the steps of:
i) mixing the acid compound of formula 4a-z and 5a-aj with EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) HOBT (Hydroxybenzotriazole), in dry DMF (Dimethylformamide) under nitrogen atmosphere with stirring at 0° C. for 15 to 20 min;
Figure US11174230-20211116-C00016
    • wherein R is selected from
Figure US11174230-20211116-C00017
    • R1 to R5 is independently selected from the group consisting of H, Cl, F, Br, CH3, C2H5, CH(CH3)2, OCH3, CF3, OCF3, OH, NO2 or CN;
    • X is selected from O, N or S.
    • ii) adding 4-(4-aminophenoxy)-N-methylpicolinamide of formula 3 in the mixture as obtained in step (i) with stirring at room temperature in the range of 20 to 30° C. for 10 to 12 h;
Figure US11174230-20211116-C00018
    • iii) cooling the mixture as obtained in step (ii), extracting, washing, drying, filtering and purifying by column chromatography to obtain compound of formula A.
    • In yet another embodiment, the solvent is DMF and DCM.
    • In yet another embodiment, the present invention provided the use of compound of formula A as anti-cancer agents
 DETAILED DESCRIPTION OF THE INVENTION
Present invention provides compound of formula A
Figure US11174230-20211116-C00019
wherein R is selected from
Figure US11174230-20211116-C00020
R1 to R5 is selected from the group consisting of H, Cl, F, Br, CH3, C2H5, CH(CH3)2, OCH3, CF3, OCF3, OH, NO2 or CN;
X is selected from O, N or S.
New (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates prepared by the known chemical reactions and procedures, in that some of the starting materials are commercially available. The major precursor 4-(4-aminophenoxy)-Nmethylpicolinamide formula 3 was prepared by using literature method (Anchoori et al. J. Med. Chem., 2008, 51, 5953-5957). Aromatic and hetero cyclic substituted acrylic acids are commercially available in the market. (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula 6a-z and 7a-aj were synthesized as illustrated in the FIGURE.
To a solution of aromatic and hetero cyclic substituted acrylic acids (4a-z and 5a-aj, mmol) in dry dimethylformamide, EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) (1.2 mmol) and HOBT (Hydroxybenzotriazole) (1.2 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (3, 1 mmol) was added and stirred at room temperature (20 to 30° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (50%) as eluent to furnish pure (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of formula 6a-z and 7a-aj in good yields (75-80%).
Aromatic and hetero cyclic substituted acrylic acids compound of formula 4a-z and 5a-aj are as follow:
Figure US11174230-20211116-C00021
Figure US11174230-20211116-C00022
Figure US11174230-20211116-C00023
Figure US11174230-20211116-C00024
Figure US11174230-20211116-C00025
Figure US11174230-20211116-C00026
Figure US11174230-20211116-C00027
Figure US11174230-20211116-C00028
The synthesis of new congeners as illustrated in the FIGURE which comprise: The acid-amine coupling reaction between 4-(4-aminophenoxy)-N-methylpicolinamide formula 3 with aromatic acrylic acid compounds of formulae 4a-z and hetero cyclic acrylic acid compounds of formulae 5a-aj for the compounds (6a-6z to 7a-7aj), respectively. These newer (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates showed promising cytotoxic activity in various cancer cell lines.
EXAMPLES
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
Example 1 (E)-4-(4-(3-(4-methoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6b)
To a solution of (E)-3-(4-methoxyphenyl)acrylic acid (89 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 157 mg (78%) of analytically pure compound (6b). mp: 202-204° C.; 1H NMR (CDCl3): δ 9.77 (s, 1H), 8.39 (d, J=5.66 Hz, 1H), 8.19 (s, 1H), 7.82 (d, J=8.87 Hz, 2H), 7.65 (q, J=7.17, 9.63 Hz, 2H), 7.52 (d, J=8.49 Hz, 3H), 7.06 (d, J=8.87 Hz, 2H), 6.98-6.90 (m, 3H), 6.66 (d, J=15.67 Hz, 1H), 3.85 (s, 3H), 2.99 (d, J=4.91 Hz, 3H); MS (ESI): m/z 404 [M+H]+.
Example 2 (E)-4-(4-(3-(2,3-dimethoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6c)
To a solution of (E)-3-(2,3-dimethoxyphenyl)acrylic acid (104.1 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (30° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 160 mg (74%) of analytically pure compound (6c). mp: 128-131° C.; 1H NMR (CDCl3): δ 8.38 (s, 1H), 8.07-8.01 (m, 2H), 7.89 (s, 1H), 7.71 (s, 1H), 7.70 (d, J=2.594 Hz, 2H), 7.12 (d, J=7.78 Hz, 1H), 7.07-7.03 (m, 3H), 6.96 (dd, J=2.44, 5.49 Hz, 1H), 6.94 (d, J=7.17 Hz, 1H), 6.68 (d, J=15.71 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.02 (d, J=5.03 Hz, 3H); MS (ESI): m/z 434 [M+H]+.
Example 3 (E)-N-methyl-4-(4-(3-(3,4,5-trimethoxyphenyl)acrylamido)phenoxy)picolinamide (6d)
To a solution of (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (119 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (20° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 182 mg (79%) of analytically pure compound (6d). mp: 148-150° C.; 1H NMR (CDCl3): δ 8.38 (s, 1H), 8.09-8.03 (m, 2H), 7.71-7.65 (m, 4H), 7.05 (d, J=8.92 Hz, 2H), 6.99 (dd, J=2.56, 5.62 Hz, 1H), 6.75 (s, 2H), 6.51 (d, J=15.52 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 6H), 3.02 (d, J=5.13 Hz, 3H); MS (ESI): m/z 464 [M+H]+.
Example 4 (E)-4-(4-(3-(2,5-dimethoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6e)
To a solution of (E)-3-(2,5-dimethoxyphenyl)acrylic acid (104.1 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 153 mg (71%) of analytically pure compound (6e). mp: 133-135° C.; 1H NMR (CDCl3): δ 8.38 (d, J=5.62 Hz, 1H), 8.03 (d, J=3.66 Hz, 1H), 7.98 (d, J=15.65 Hz, 1H), 7.74 (s, 1H), 7.70 (d, J=2.32 Hz, 2H), 7.68 (s, 1H), 708-7.03 (m, 3H), 6.96 (dd, J=2.56, 5.50 Hz, 1H), 6.89 (d, J=2.93 Hz, 1H), 6.87 (d, J=8.92 Hz, 1H), 6.70 (d, J=15.65 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.02 (d, J=5.13 Hz, 3H); MS (ESI): m/z 434 [M+H]+.
Example 5 (E)-4-(4-(3-(3-hydroxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6g)
To a solution of (E)-3-(3-hydroxyphenyl)acrylic acid (82 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 136 mg (70%) of analytically pure compound (6g). mp: 180-182° C.; 1H NMR (CDCl3): δ 9.89 (s, 1H), 9.14 (s, 1H), 8.40 (d, J=5.66 Hz, 1H), 8.20 (d, J=4.91 Hz, 1H), 7.82 (d, J=8.87 Hz, 2H), 7.66-7.53 (m, 3H), 7.21 (t, J=7.93 Hz, 1H), 7.07-7.00 (s, 4H), 6.97 (dd, J=2.45, 5.66 Hz, 1H), 6.86 (dd, J=1.51, 7.93 Hz, 1H), 6.75 (d, J=15.48 Hz, 1H), 2.99 (d, J=5.09 Hz, 3H); MS (ESI): m/z 390 [M+H]+.
Example 6 (E)-4-(4-(3-(4-chlorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6l)
To a solution of (E)-3-(4-chlorophenyl)acrylic acid (91.3 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 146 mg (72%) of analytically pure compound (6l). mp: 192-195° C.; 1H NMR (CDCl3): δ 8.39 (d, J=5.64 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J=4.88 Hz, 1H), 7.72-7.67 (m, 3H), 7.65 (d, J=2.44 Hz, 1H), 7.42 (d, J=8.54 Hz, 2H), 7.34 (d, J=8.39 Hz, 2H), 7.04 (d, J=8.85 Hz, 2H), 6.99 (dd, J=2.44, 5.49 Hz, 1H), 6.56 (d, J=15.41 Hz, 1H), 3.02 (d, J=5.18 Hz, 3H); MS (ESI): m/z 408 [M+H]+.
Example 7 (E)-4-(4-(3-(4-fluorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6o)
To a solution of (E)-3-(4-fluorophenyl)acrylic acid (83 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 150 mg (77%) of analytically pure compound (6o). mp: 222-224° C.; 1H NMR (CDCl3+DMSO): δ 9.79 (s, 1H), 8.39 (d, J=5.47 Hz, 1H), 8.15 (d, J=4.15 Hz, 1H), 7.81 (d, J=8.87 Hz, 2H), 7.71-7.64 (m, 2H), 7.56 (q, J=5.47, 8.49 Hz, 2H), 7.13-7.03 (m, 4H), 6.97 (dd, J=2.45, 5.66 Hz, 1H), 6.72 (d, J=15.67 Hz, 1H), 3.00 (d, J=5.09 Hz, 3H); MS (ESI): m/z 392 [M+H]+.
Example 8 (E)-4-(4-(3-(3,4-difluorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6q)
To a solution of (E)-3-(3,4-difluorophenyl)acrylic acid (92 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 155 mg (76%) of analytically pure compound (6q). mp: 208-210° C.; 1H NMR (CDCl3): δ 8.40 (d, J=5.62 Hz, 2H), 8.10 (d, J=4.76 Hz, 1H), 7.70 (d, J=8.55 Hz, 2H), 7.64 (d, J=15.89 Hz, 2H), 7.06-7.00 (m, 3H), 6.96 (d, J=6.11 Hz, 2H), 6.84-6.78 (m, 1H), 6.58 (d, J=15.52 Hz, 1H), 3.03 (d, J=5.13 Hz, 3H); MS (ESI): m/z 410 [M+H]+.
Example 9 (E)-N-methyl-4-(4-(3-(4-(trifluoromethyl)phenyl)acrylamido)phenoxy)picolinamide (6t)
To a solution of (E)-3-(4-(trifluoromethyl)phenyl)acrylic acid (94.5 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 163 mg (74%) of analytically pure compound (6t). mp: 210-212° C.; 1H NMR (CDCl3+DMSO): δ 10.06 (s, 1H), 8.40 (d, J=5.47 Hz, 1H), 8.23 (d, J=4.72 Hz, 1H), 7.83 (d, J=8.87 Hz, 2H), 7.73 (d, J=9.25 Hz, 1H), 7.70-7.63 (m, 5H), 7.08 (d, J=8.87 Hz, 2H), 6.98 (dd, J=2.45, 5.47 Hz, 1H), 6.92 (d, J=15.67 Hz, 1H), 2.99 (d, J=5.09 Hz, 3H); MS (ESI): m/z 442 [M+H]+.
Example 10 (E)-N-methyl-4-(4-(3-(4-(trifluoromethoxy)phenyl)acrylamido)phenoxy)picolinamide (6w)
To a solution of (E)-3-(4-(trifluoromethoxy)phenyl)acrylic acid (116 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 173 mg (76%) of analytically pure compound (6w). mp: 198-200° C.; 1H NMR (CDCl3+DMSO): δ 10.01 (s, 1H), 8.39 (d, J=4.34 Hz, 1H), 8.20 (s, 1H), 7.83 (d, J=7.74 Hz, 2H), 7.56-7.40 (m, 4H), 7.23 (d, J=4.53 Hz, 1H), 7.07 (d, J=7.93 Hz, 2H), 6.97 (s, 1H), 6.86 (d, J=15.67 Hz, 1H), 3.01 (d, J=6.04 Hz, 3H); MS (ESI): m/z 458 [M+H]+.
Example 11 (E)-4-(4-(3-(furan-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7b)
To a solution of (E)-3-(furan-2-yl)acrylic acid (69 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 127 mg (70%) of analytically pure compound (7b). mp: 163-165° C.; 1H NMR (CDCl3): δ 8.38 (d, J=5.64 Hz, 1H), 8.04 (d, J=4.42 Hz, 1H), 7.88 (s, 1H), 7.69 (d, J=2.28 Hz, 2H), 7.67 (s, 1H), 7.53 (d, J=15.10 Hz, 1H), 7.45 (s, 1H), 7.04 (d, J=8.85 Hz, 2H), 6.96 (q, J=2.59, 5.64 Hz, 1H), 6.60 (d, J=3.35 Hz, 1H), 6.49 (d, J=14.95 Hz, 1H), 6.47 (d, J=1.83 Hz, 1H), 3.02 (d, J=5.18 Hz, 3H); MS (ESI): m/z 364 [M+H]+.
Example 12 (E)-N-methyl-4-(4-(3-(thiophen-2-yl)acrylamido)phenoxy)picolinamide (7g)
To a solution of (E)-3-(thiophen-2-yl)acrylic acid (77 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0° C. and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25° C.) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3×15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 140 mg (74%) of analytically pure compound (7g). mp: 183-185° C.; 1H NMR (CDCl3): δ 8.38 (d, J=5.49 Hz, 1H), 8.05 (d, J=4.73 Hz, 1H), 7.90 (s, 1H), 7.87 (d, J=15.25 Hz, 1H), 7.68 (q, J=3.20, 5.79 Hz, 3H), 7.34 (d, J=5.03 Hz, 1H), 7.25 (d, J=3.35 Hz, 1H), 7.07-7.03 (m, 3H), 6.97 (dd, J=2.59, 5.49 Hz, 1H), 6.38 (d, J=15.10 Hz, 1H), 3.02 (d, J=5.18 Hz, 3H); MS (ESI): m/z 380 [M+H]+.
Biological Activity
The cytotoxic activity studies for these (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates were carried out at the Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
Cytotoxic Activity
The (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates of general formulae 6a-6z and 7a-7aj have been evaluated for their cytotoxicity in selected human cancer cell lines i.e., lung (A549), prostate (DU-145), ovarian (SKOV3) and liver (HepG2) using MTT assay and the values obtained were compared to a standard drug sorafenib, with the concentration (treatment done at ranging from 10−4 to 10−8 M) of the compound produces to 50% inhibition of cell growth (IC50) as shown in Table 1. The screening results suggested that the selected compounds 6b, 6c, 6d, 6e, 6g, 6l, 6m, 6o, 6p, 6q, 6t, 6z, 7b and 7g exhibit significant cytotoxicity against a different set of human cancer cell lines. The IC50 values (in μM) for compounds 6b, 6c, 6d, 6e, 6g, 6l, 6m, 6o, 6p, 6q, 6t, 6z, 7b and 7g have been illustrated in Table 1.
From the Table 1, it is seen that compounds 6b, 6c, 6d, 6e, 6g, 6l, 6m, 6o, 6p, 6q, 6t, 6z, 7b and 7g exhibit significant activity more specifically against HepG2 (liver cancer) among the four different types of cancer cell lines examined, with IC50 values ranging from 8 to 13 μM. Predominantly, these compounds show superior cytotoxicity than the standard drug sorafenib i.e. 14.5 μM on HepG2 (liver cancer) cell line. Moreover, compound 6t exhibits remarkable cytotoxicity (8.2 μM) compared to other compounds has revealed in the Table 1. In the same way, the compounds 6b, 6l, 6d, 6e and 7b were more potent than the other compounds like 6c, 6g, 6m, 6o, 6p, 6q, 6z and 7g. The IC50 values (in μM) for the compounds 6b, 6d, 6e, 6l and 7b against HepG2 (liver cancer) cell line were 9.5, 10.2, 10.1, 9.6 and 10.2 μM respectively.
TABLE 1
IC50 values (in μM) for compounds in selected
human cancer cell lines
Com-
pounda A549b DU145c SKOV3d HepG2e
6b — — 10.6 ± 0.32  9.5 ± 0.08
6c — — — 12.4 ± 0.16
6d — 21.1 ± 0.18 — 10.2 ± 0.22
6e — 29.5 ± 0.26 — 10.1 ± 0.15
6g — — 12.0 ± 0.11 10.9 ± 0.22
6l — 17.9 ± 0.24 12.6 ± 0.28  9.6 ± 0.16
6m  9.5 ± 0.22 23.3 ± 0.28 — 12.4 ± 0.32
6o — — — 12.5 ± 0.18
6p 49.4 ± 0.54 — — 13.1 ± 0.26
6q — — 11.2 ± 0.26 11.1 ± 0.14
6t 22.3 ± 0.22 — —  8.2 ± 0.09
6z 30.1 ± 0.28 28.7 ± 0.36 — 12.2 ± 0.22
7b — — — 10.2 ± 0.11
7g 24.1 ± 0.44 12.2 ± 0.26 — 13.2 ± 0.11
Sorafenib  6.1 ± 0.18  6.5 ± 0.22  9.5 ± 0.12 14.5 ± 0.16
a50% Inhibitory concentration after 48 h of drug treatment and the values are average of three individual experiments,
bHuman lung cancer,
cHuman prostate cancer,
dHuman ovarian cancer,
eLiver cancer.
Advantages of the Invention
The present invention provides some new (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates useful as antitumor agents. In this present invention, the synthesized compounds have shown significant anticancer activity.
(E)-4-(4-Acrylamidophenoxy)-N-methylpicolinamide conjugates that have been synthesized exhibited potent cytotoxic activity against different human tumor cell lines.
It also provides a process for the preparation of new (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates.

Claims (6)

We claim:
1. A compound of formula A:
Figure US11174230-20211116-C00029
wherein R is selected from
Figure US11174230-20211116-C00030
where R1 to R5 are independently selected from the group consisting of H, Cl, F, Br, CH3, C2H5, CH(CH3)2, OCH3, CF3, OCF3, OH, NO2, and CN; and
X is selected from O, NH, or S.
2. The compound according to claim 1, wherein the compound is selected from the group consisting of:
(E)-4-(4-(3-(2-methoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6a);
(E)-4-(4-(3-(4-methoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6b);
(E)-4-(4-(3-(2,3-dimethoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6c);
(E)-N-methyl-4-(4-(3-(3,4,5-trimethoxyphenyl)acrylamido)phenoxy)picolinamide (6d);
(E)-4-(4-(3-(2,5-dimethoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6e);
(E)-4-(4-(3-(3,4-dimethoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6f);
(E)-4-(4-(3-(3-hydroxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6g);
(E)-4-(4-(3-(4-hydroxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6h);
(E)-4-(4-(3-(3-hydroxy-4-methoxyphenyl)acrylamido)phenoxy)-N-methylpicolinamide (6i);
(E)-4-(4-(3-(2-chlorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6j);
(E)-4-(4-(3-(3-chlorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6k);
(E)-4-(4-(3-(4-chlorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6l);
(E)-4-(4-(3-(3,4-dichlorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6m);
(E)-4-(4-(3-(3-fluorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6n);
(E)-4-(4-(3-(4-fluorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6o);
(E)-4-(4-(3-(2,4-difluorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6p);
(E)-4-(4-(3-(3,4-difluorophenyl)acrylamido)phenoxy)-N-methylpicolinamide (6q);
(E)-N-methyl-4-(4-(3-(2-(trifluoromethyl)phenyl)acrylamido)phenoxy)picolinamide (6r);
(E)-N-methyl-4-(4-(3-(3-(trifluoromethyl)phenyl)acrylamido)phenoxy)picolinamide (6s);
(E)-N-methyl-4-(4-(3-(4-(trifluoromethyl)phenyl)acrylamido)phenoxy)picolinamide (6t);
(E)-N-methyl-4-(4-(3-(2-(trifluoromethoxy)phenyl)acrylamido)phenoxy)picolinamide (6u);
(E)-N-methyl-4-(4-(3-(3-(trifluoromethoxy)phenyl)acrylamido)phenoxy)picolinamide (6v);
(E)-N-methyl-4-(4-(3-(4-(trifluoromethoxy)phenyl)acrylamido)phenoxy)picolinamide (6w);
(E)-4-(4-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)acrylamido)phenoxy)-N-methylpicolinamide (6x);
(E)-4-(4-(3-(4-chloro-3-(trifluoromethoxy)phenyl)acrylamido)phenoxy)-N-methylpicolinamide (6y);
(E)-N-methyl-4-(4-(3-(4-nitrophenyl)acrylamido)phenoxy)picolinamide (6z);
(E)-4-(4-(3-(1H-pyrrol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7a);
(E)-4-(4-(3-(furan-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7b);
(E)-N-methyl-4-(4-(3-(5-methylfuran-2yl)acrylamido)phenoxy)picolinamide (7c);
(E)-4-(4-(3-(5-ethylfuran-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7d);
(E)-4-(4-(3-(3-bromofuran-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7e);
(E)-N-methyl-4-(4-(3-(5-nitrofuran-2-yl)acrylamido)phenoxy)picolinamide (7f);
(E)-N-methyl-4-(4-(3-(thiophen-2-yl)acrylamido)phenoxy)picolinamide (7g);
(E)-4-(4-(3-(4-bromothiophen-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7h);
(E)-N-methyl-4-(4-(3-(3-methylthiophen-2-yl)acrylamido)phenoxy)picolinamide (7i);
(E)-4-(4-(3-(5-cyanothiophen-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7j);
(E)-N-methyl-4-(4-(3-(4-methylthiophen-2-yl)acrylamido)phenoxy)picolinamide (7k);
(E)-N-methyl-4-(4-(3-(5-methylthiophen-2-yl)acrylamido)phenoxy)picolinamide (7l);
(E)-4-(4-(3-(benzofuran-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7m);
(E)-4-(4-(3-(7-methoxybenzofuran-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7n);
(E)-4-(4-(3-(benzo[b]thiophen-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7o);
(E)-4-(4-(3-(3-bromobenzo[b]thiophen-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (′7p);
(E)-N-methyl-4-(4-(3-(3-methylbenzo[b]thiophen-2-yl)acrylamido)phenoxy)picolinamide (7q);
(E)-4-(4-(3-(3-chlorobenzo[b]thiophen-2-yl)acrylamido)phenoxy)-N-methylpicolinamide (7r);
(E)-N-methyl-4-(4-(3-(5-methylbenzo[b]thiophen-2-yl)acrylamido)phenoxy)picolinamide (7s);
(E)-N-methyl-4-(4-(3-(4-methylbenzo[b]thiophen-2-yl)acrylamido)phenoxy)picolinamide (7t);
(E)-4-(4-(3-(1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7u);
(E)-N-methyl-4-(4-(3-(7-methyl-1H-indol-3-yl)acrylamido)phenoxy)picolinamide (7v);
(E)-4-(4-(3-(7-ethyl-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7w);
(E)-4-(4-(3-(6-isopropyl-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7x);
(E)-4-(4-(3-(5-chloro-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (′7y);
(E)-4-(4-(3-(6-chloro-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7z);
(E)-4-(4-(3-(5-fluoro-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7aa);
(E)-4-(4-(3-(6-fluoro-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7ab);
(E)-4-(4-(3-(5-bromo-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7ac);
(E)-4-(4-(3-(6-bromo-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7ad);
(E)-4-(4-(3-(5-cyano-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7ae);
(E)-4-(4-(3-(6-cyano-1H-indol-3-yl)acrylamido)phenoxy)-N-methylpicolinamide (7af);
(E)-N-methyl-4-(4-(3-(5-methyl-1H-indol-3-yl)acrylamido)phenoxy)picolinamide (7ag);
(E)-N-methyl-4-(4-(3-(6-methyl-1H-indol-3-yl)acrylamido)phenoxy)picolinamide (7ah);
(E)-N-methyl-4-(4-(3-(5-nitro-1H-indol-3-yl)acrylamido)phenoxy)picolinamide (7a1); and
(E)-N-methyl-4-(4-(3-(6-nitro-1H-indol-3-yl)acrylamido)phenoxy)picolinamide (7aj).
3. The compound according to claim 1, wherein said compound exhibits cytotoxic activity against cancer cell lines selected from the group consisting of non-small cell lung cancer, colon cancer, prostate cancer, ovarian cancer, and liver cancer.
4. The compound according to claim 1, wherein an IC50 value for 50% inhibition of cell growth of cancer cells of the compound of formula A, using in-vitro MTT assay is in the range of 8 μM to 13 μM.
5. A process for the preparation of compounds of formula A, the process comprising:
(i) mixing acid compound of formula 4 with 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide and Hydroxybenzotriazole, under stirring at a temperature in the range of 0 to 10° C. for 15 to 20 minutes in a solvent to obtain a mixture;
Figure US11174230-20211116-C00031
wherein R is selected from
Figure US11174230-20211116-C00032
where R1 to R5 is independently are independently selected from the group consisting of H, Cl, F, Br, CH3, C2H5, CH(CH3)2, OCH3, CF3, OCF3, OH, NO2 and CN; and
X is selected from O, NH, or S;
(ii) adding 4-(4-aminophenoxy)-N-methylpicolinamide of formula 3 in the mixture as obtained in (i) with stirring at a temperature in the range of 20 to 30° C. for 10 to 12 hours to obtain a mixture; and
Figure US11174230-20211116-C00033
(iii) cooling the mixture as obtained in (ii), extracting, washing, drying, filtering and purifying by column chromatography to obtain the compound of formula A:
Figure US11174230-20211116-C00034
6. The process according to claim 5, wherein the solvent is dimethylformamide (DMF) and DCM.
US16/071,105 2016-01-20 2017-01-04 (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide conjugates as potential anticancer agents Active 2038-11-14 US11174230B2 (en)

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